The innate immune response in a human or mammal clears the infection and/or provides prophylactic protection against pathogenic challenge. The innate immune response is a nonspecific immune response generated by the host in response to infection by pathogenic organisms. It is independent of T cells, and occurs very rapidly after infection. The principal cells involved in mounting an innate immune response include the cells of the mononuclear phagocyte system (e.g. macrophages), granulocytes, and natural killer (NK) cells. Macrophages function in innate immunity to phagocytose and degrade foreign particles; secrete enzymes, reactive oxygen species, nitric oxide, and lipid-derived mediators (e.g. prostaglandins) which serve to kill pathogenic organisms and control the spread of infection; and produce cytokines that recruit other inflammatory cells to the site of infection, such as neutrophils. Granulocytes include neutrophils, eosinophils, and basophils, and are important in generating an inflammatory response. Natural Killer cells are a subset of lymphocytes that do not require prior contact with an antigen to become cytotoxic, but rather are activated by stimulation from cytokines such as type I IFN, IFN-γ, IL-12, TNF or IL-2.
Upon infection by a pathogenic organism, one of the first cellular responses is increased transcription of IRF-3 in the infected cell(s), which results in increased production of type I IFN (e.g. IFN-α and IFN-β). IFN-β acts in a paracrine fashion on neighboring cells to cause them to produce IFN-γ, which in turn acts on macrophages, resulting in their activation. Activated macrophages produce more cytokines, have increased microbicidal activity, and participate in the specific immune response by presenting antigens to lymphocytes. Type I IFNs also increase the expression of iNOS, an enzyme responsible for generating nitric oxide (NO), which is toxic to pathogens. Additionally, type I IFNs increase the lytic activity of NK cells, and help to recruit them to the site of infection.
Traditionally, bacterial infections have been treated through the use of various antibiotics, which usually comprise chemical compounds that are either toxic to the bacteria or interfere with bacterial metabolism sufficiently that growth is inhibited and/or killing occurs. However, bacteria evolve very rapidly, and are capable of transferring antibiotic resistance across species. This has resulted in an increased resistance among bacteria to traditional antibiotics. Therapy of viral infections has been modeled after that of bacterial infections. However, application of the principles of antibacterial therapy to antiviral therapy (and prophylaxis) presents a number of unique problems. A major challenge is identifying antiviral compounds that are relatively non-toxic to mammalian cells because, unlike bacteria, viruses must replicate intracellularly and often employ host cell biomolecules and organelles for the synthesis of virus particles. Consequently, antiviral agents are available to treat only a few viral diseases because any drug that interferes significantly with viral replication is likely to be toxic to the host.
Accordingly, a need remains for effective antibacterial agents that can avoid bacterial mechanisms of resistance, as well as for safe and effective antiviral agents with a broad spectrum of antiviral activity and reduced toxicity to the host.
Flavonoids, which are found ubiquitously in photosynthesizing plant cells, induce biologic effects in humans and other animals, ranging from the induction of cytokines such as interferon gamma (IFN-γ) in lymphocytes to the inhibition of a number of key metabolic regulatory enzymes. Because of the potential therapeutic effects of flavonoids, and their low toxicity profile in experimental animals, several synthetic flavonoids have been screened for antitumor activity (see, e.g., U.S. Pat. No. 5,126,129), antiviral activity (see, e.g., U.S. Pat. Nos. 6,274,611; 6,399,654 and 7,166,640; WO 01/03681), and antiparasitic activity (see, e.g., U.S. Pat. No. 5,977,077).
Flavone acetic acid analogues (FAA) comprise a class of flavonoids. DMXAA (5,6-dimethylxanthenone-4-acetic acid) is an analogue of flavone acetic acid (FAA) and, like FAA, causes the ischemic hemorrhagic necrosis of solid tumors in mice. Additionally, FAA and DMXAA both induce the synthesis of tumor necrosis factor alpha (TNF-α), stimulates the production of nitric oxide, and activates macrophages to be tumoricidal. However, DMXAA is more effective and 12-fold more potent in vivo against murine colon tumors than FAA, and DMXAA induces cytokine production in both human and murine cell lines, whereas FAA acts on human cells in vitro but does not exert anti-tumor effects in humans in vivo and has undesirable side effects. For example, DMXAA has been shown to induce the production of TNF-α mRNA in the myelomonocytic human cell line HL-60 and in human peripheral blood leukocytes (Aitken et al. (1996) “Synthesis And Antitumor Activity Of New Derivatives Of Flavone-8-Acetic Acid (FAA). Part 1: 6-Methyl Derivatives,” Arch. Pharm. (Weinheim) 329(11):489-497; Aitken et al. (1997) “Synthesis And Antitumor Activity Of New Derivatives Of Flavone-8-Acetic Acid (FAA). Part 2: Ring-Substituted Derivatives,” Arch. Pharm. (Weinheim) 330(7):215-224; Aitken et al. (1998) “Synthesis and antitumor activity of new derivatives of flavone-8-acetic acid (FAA). Part 3: 2-Heteroaryl derivatives,” Arch. Pharm. (Weinheim) 331(12): 405-411; Aitken et al. (2000) “Synthesis And Antitumor Activity Of New Derivatives Of Flavone-8-Acetic Acid (FAA). Part 4: Variation Of The Basic Structure,” Arch. Pharm. (Weinheim) 333(6):181-188; Baguley, B. C. (2001) “Small-Molecule Cytokine Inducers Causing Tumor Necrosis”, Curr. Opin. Investig. Drugs 2(7):967-975; Gobbi et al. (2006) “New Derivatives Of Xanthenone-4-Acetic Acid: Synthesis, Pharmacological Profile And Effect On TNF-Alpha And NO Production In Human Immune Cells,” Bioorg. Med. Chem. 14(12):4101-4109; Philpott et al. (1997) “Production Of Tumor Necrosis Factor Alpha By Cultured Human Peripheral Blood Leucocytes In Response To The Anti-Tumor Agent 5,6-Dimethylxanthenone-4-Acetic Acid (NSC 640488),” Br. J. Cancer 76(12):1586-1591; Zhou et al. (2002) “5,6-Dimethylxanthenone-4-Acetic Acid (DMXAA): A New Biological Response Modifier For Cancer Therapy,” Invest. New Drugs 20(3):281-295).
Thus, despite all previous efforts, a need remains for improved antimicrobial agents. The present invention is directed to this and other goals.